Adolescent female rats prone to the activity based anorexia (ABA) paradigm have altered hedonic responses and cortical astrocyte density compared to resistant animals.

OBJECTIVE: Anhedonia, which in part involves the lack of pleasure in consuming palatable food, is a long-lasting symptom observed in patients both when acutely ill and when long term recovered from Anorexia Nervosa. The neurocircuitry underlying this phenomenon is not well understood. Here we use the preclinical activity-based anorexia (ABA) model in adolescent female rats to assess the impact of excessive exercise, limited food intake and acute weight loss, on adolescent female rat orofacial responding to intraoral sucrose, as measured by the taste reactivity test (TRT). Animals were identified as either prone or resistant to this paradigm based on a weight loss criterion. Measures of food intake, running wheel activity, taste reactivity and medial prefrontal cortex astrocyte expression were compared across groups. METHODS: Adolescent female rats implanted with an intraoral catheter were given a TRT using 1 M (M) sucrose at baseline, max weight loss (25% weight loss from start of ABA or 7 full days on the paradigm) or 10 days recovered from the ABA paradigm. Animals were sacrificed after the final TRT and astrocyte density was measured via immunohistochemistry. RESULTS: Animals resistant to the ABA paradigm ran less than prone animals during the ABA period. Additionally, we found that resistant animals displayed more cumulative 'liking' responses to sucrose compared to prone animals at maximum weight loss. Finally, we found prone animals 10-days recovered from ABA had reduced medial prefrontal cortex astrocyte density compared to levels in resistant animals. DISCUSSION: Rats presented with the physiological challenge of the ABA paradigm either adapt their behavior to stabilize their body weight (i.e. resistant), or rapidly lose weight (i.e. prone). Furthermore, we found that prone animals have reduced orofacial responding to 1 M sucrose at maximum weight loss compared to responses in resistant animals, and this anhedonia-like behavior may be a result of reduced astrocyte density that affects cortical function.

Gastrointestinal symptomatology, diagnosis, and treatment history in patients with underweight avoidant/restrictive food intake disorder and anorexia nervosa: Impact on weight restoration in a meal-based behavioral treatment program.

OBJECTIVE: Gastrointestinal (GI) concerns are often presumed to complicate nutritional rehabilitation for restrictive eating disorders, yet their relationship to weight restoration outcomes is unclear. This retrospective chart review examined GI history and weight-related discharge outcomes in primarily adult, underweight inpatients with anorexia nervosa (AN, N = 107) or avoidant/restrictive food intake disorder (ARFID, N = 22) treated in a meal-based, behavioral eating disorder program. METHOD: Lifetime GI symptomatology, diagnoses, diagnostic tests, and procedures were abstracted from medical records. Generalized linear models examined associations of GI diagnoses, tests, and procedures with discharge BMI and rate of weight gain. RESULTS: Ninety-nine percent of patients reported GI symptomatology and 83% had one or more GI diagnoses; with constipation and GERD most common. GI diagnoses (p <.01) and testing (p <.001) were more common in ARFID than AN. Average inpatient weight gain (1.59 kg/week), and discharge BMI (18.5 kg/m2 ), did not differ by group. Slower weight gain in patients with (1.3 kg/week), versus without (1.7 kg/week), history of tube feeding (p = .02), accounted for a main effect of GI procedures on inpatient rate of gain (p = .01). DISCUSSION: Despite ubiquitous GI symptomatology, meal-based weight restoration achieved average weekly weight gain above recommended APA guidelines for hospitalized patients with an eating disorder. History of tube feeding was associated with slower mean weight gain, which remained, however, within recommended APA guidelines.

Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer.

OBJECTIVES: To determine the performance of Prostate Health Index (PHI) density (PHID) combined with MRI and prior negative biopsy (PNB) status for the diagnosis of clinically significant prostate cancer (PCa). PATIENTS AND METHODS: Patients without a prior diagnosis of PCa, with elevated prostate-specific antigen and a normal digital rectal examination who underwent PHI testing prospectively prior to prostate biopsy were included in this study. PHID was calculated retrospectively using prostate volume derived from transrectal ultrasonography at biopsy. Univariable and multivariable logistic regression modelling, along with receiver-operating characteristic (ROC) curve analysis, was used to determine the ability of serum biomarkers to predict clinically significant PCa (defined as either grade group [GG] ≥2 disease or GG1 PCa detected in >2 cores or >50% of any one core) on biopsy. Age, PNB status and Prostate Imaging Reporting and Data System (PI-RADS) score were incorporated into the regression models. RESULTS: Of the 241 men who qualified for the study, 91 (37.8%) had clinically significant PCa on biopsy. The median (interquartile range) PHID was 0.74 (0.44-1.24); it was 1.18 (0.77-1.83) and 0.55 (0.38-0.89) in those with and without clinically significant PCa on biopsy, respectively (P < 0.001). On univariable logistic regression, age and PNB status were associated with clinically significant cancer. Of the tested biomarkers, PHID demonstrated the highest discriminative ability for clinically significant disease (area under the ROC curve [AUC] 0.78 for the univariable model). That continued to be the case in multivariable logistic regression models incorporating age and PNB status (AUC 0.82). At a threshold of 0.44, representing the 25th percentile of PHID in the cohort, PHID was 92.3% sensitive and 35.3% specific for clinically significant PCa; the sensitivity and specificity were 93.0% and 32.4% and 97.4% and 29.1% for GG ≥2 and GG ≥3 disease, respectively. In the 104 men who underwent MRI, PI-RADS score was complementary to PHID, with a PI-RADS score ≥3 or, if PI-RADS score ≤2, a PHID ≥0.44, detecting 100% of clinically significant disease. For that subgroup, of the biomarkers tested, PHID (AUC 0.90) demonstrated the highest discriminative ability for clinically significant disease on multivariable logistic regression incorporating age, PNB status and PI-RADS score. CONCLUSIONS: In this contemporary cohort of men undergoing prostate biopsy for the diagnosis of PCa, PHID outperformed PHI and other PSA derivatives in the diagnosis of clinically significant cancer. Incorporating age, PNB status and PI-RADS score led to even further gains in the diagnostic performance of PHID. Furthermore, PI-RADS score was found to be complementary to PHID. Using 0.44 as a threshold for PHID, 35.3% of unnecessary biopsies could have been avoided at the cost of missing 7.7% of clinically significant cancers. Despite these encouraging results, prospective validation is needed.

Analysis of Hospital Readmissions After Prosthetic Urologic Surgery in the United States: Nationally Representative Estimates of Causes, Costs, and Predictive Factors.

BACKGROUND: The surgical treatment of urinary incontinence and erectile dysfunction by prosthetic devices has become part of urologic practice, although sparse data exist at a national level on readmissions and hospital costs. AIM: To assess causes and costs of early (≤30 days) and late (31-90 days) readmissions after implantation of penile prostheses (PPs), artificial urinary sphincters (AUSs), or PP + AUS. METHODS: Using the 2013 and 2014 US Nationwide Readmission Databases, sociodemographic characteristics, hospital costs, and causes of readmission were compared among PP, AUS and AUS + PP surgeries. Multivariable logistic regression models tested possible predictors of hospital readmission (early, late, and 90 days), increased hospital costs, and prolonged length of stay at initial hospitalization and readmission. OUTCOME: Outcomes were rates, causes, hospital costs, and predictive factors of early, late, and any 90-day readmissions. RESULTS: Of 3,620 patients, 2,626 (73%) had PP implantation, 920 (25%) had AUS implantation, and 74 (2%) underwent PP + AUS placement. In patients undergoing PP, AUS, or PP + AUS placement, 30-day (6.3% vs 7.9% vs <15.0%, P = .5) and 90-day (11.6% vs 12.8% vs <15.0%, P = .8) readmission rates were comparable. Early readmissions were more frequently caused by wound complications compared with late readmissions (10.9% vs <4%, P = .03). Multivariable models identified longer length of stay, Charlson Comorbidity Index score higher than 0, complicated diabetes, and discharge not to home as predictors of 90-day readmissions. Notably, hospital volume was not a predictor of early, late, or any 90-day readmissions. However, within the subset of high-volume hospitals, each additional procedure was associated with increased risk of late (odds ratio = 1.06, 95% CI = 1.03-1.09, P < .001) and 90-day (odds ratio = 1.03 95% CI = 1.02-1.05, P < .001) readmissions. AUS and PP + AUS surgeries had higher initial hospitalization costs (P < .001). A high hospital prosthetic volume decreased costs at initial hospitalization. Mechanical complications led to readmission of all patients receiving PP + AUS. CLINICAL IMPLICATIONS: High-volume hospitals showed a weaker association with increased initial hospitalization costs. Charlson Comorbidity Index, diabetes, and length of stay were predictors of 90-day readmission, showing that comorbidity status is important for surgical candidacy. STRENGTHS AND LIMITATIONS: This is the first study focusing on readmissions and costs after PP, AUS, and PP + AUS surgeries using a national database, which allows ascertainment of readmissions to hospitals that did not perform the initial surgery. Limitations are related to the limited geographic coverage of the database and lack of surgery- and surgeon-specific variables. CONCLUSIONS: Analysis of readmissions can provide better care for urologic prosthetic surgeries through better preoperative optimization, counseling, and resource allocation. Pederzoli F, Chappidi MR, Collica S, et al. Analysis of Hospital Readmissions After Prosthetic Urologic Surgery in the United States: Nationally Representative Estimates of Causes, Costs, and Predictive Factors. J Sex Med 2017;14:1059-1065.

Predictors of Late-Onset Atrial Fibrillation Following Isolated Mitral Valve Repairs in Patients With Preserved Ejection Fraction.

BACKGROUND: We sought to determine the incidence of and risk factors for late-onset atrial fibrillation (LOAF) in patients with preserved ejection fractions undergoing mitral valve repair METHODS: We included patients undergoing isolated mitral valve repair (MVR) for degenerative disease between 1997-2014 at our institution with EF ≥60%. Patients who had AF preoperatively were excluded from the final analysis. Our primary outcome, LOAF, was defined as AF occurring after discharge following MVR (≥9 days). RESULTS: 223 patients were included in the study with a mean follow-up of 4.8 ± 4.6 years. A total of 25 patients developed LOAF, and freedom from LOAF was 93.9% at one year, and 87.3% at five years. Patients developing LOAF were of similar mean age (58 vs. 63 years in controls, p = 0.08) and had similar preoperative comorbidities, but did show a trend toward larger left atrial diameter (5.1 vs. 4.7 cm, p = 0.11). After risk adjustment with Cox regression analysis, only increasing left atrial size was associated with LOAF (HR 1.63, p = 0.04). On follow-up, 29 patients (10.8%) developed moderate or greater mitral regurgitation at a mean of 2.2 years. Using a mixed-effects model, we were unable to detect an association between recurrent mitral regurgitation following MVR and LOAF (OR 1.36, p = 0.42). CONCLUSIONS: LOAF occurs in about 13% of preserved ejection fraction patients undergoing MVR by five years. Increasing left atrial diameter is an independent predictor of LOAF. Concomitant anti-arrhythmic procedures may warrant further investigation in patients with preserved ejection fraction and enlarged left atria undergoing MVR. doi: 10.1111/jocs.12774 (J Card Surg 2016;31:486-492).

AMPK agonist AICAR improves cognition and motor coordination in young and aged mice.

Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced spatial memory function, and endurance. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (5- to 7-wk-old) and aged (23-mo-old) female C57Bl/6 mice, and in young (4- to 6-wk-old) transgenic mice with muscle-specific mutated AMPK α2-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3-14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice. In the AMPK-DN mice, the compound did not enhance behavior, providing support for a muscle-mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus, genes relevant to neuronal development and plasticity were enriched. Altogether, endurance-related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions.

Neonatal loss of FGFR2 in astroglial cells affects locomotion, sociability, working memory, and glia-neuron interactions in mice.

Fibroblast growth factor receptor 2 (FGFR2) is almost exclusively expressed in glial cells in postnatal mouse brain, but its impact in glia for brain behavioral functioning is poorly understood. We compared behavioral effects from FGFR2 loss in both neurons and astroglial cells and from FGFR2 loss in astroglial cells by using either the pluripotent progenitor-driven hGFAP-cre or the tamoxifen-inducible astrocyte-driven GFAP-creERT2 in Fgfr2 floxed mice. When FGFR2 was eliminated in embryonic pluripotent precursors or in early postnatal astroglia, mice were hyperactive, and had small changes in working memory, sociability, and anxiety-like behavior. In contrast, FGFR2 loss in astrocytes starting at 8 weeks of age resulted only in reduced anxiety-like behavior. Therefore, early postnatal loss of FGFR2 in astroglia is critical for broad behavioral dysregulation. Neurobiological assessments demonstrated that astrocyte-neuron membrane contact was reduced and glial glutamine synthetase expression increased only by early postnatal FGFR2 loss. We conclude that altered astroglial cell function dependent on FGFR2 in the early postnatal period may result in impaired synaptic development and behavioral regulation, modeling childhood behavioral deficits like attention deficit hyperactivity disorder (ADHD).

Attributable harm of severe bleeding after cardiac surgery in hemodynamically stable patients.

BACKGROUND: We sought to quantify the effect of severe postoperative bleeding in hemodynamically stable patients following cardiac surgery. METHODS: We reviewed the charts of all cardiac surgery patients operated on at our institution between 2010 and 2014. After excluding patients with tamponade or MAP <60, we propensity matched patients having chest tube output >300 mL in the first postoperative hour, >200 mL in the second, and >100 mL in the third ("bleeding" group) with patients having <50 mL/h of chest tube output ("dry" group). The primary outcome was a composite of morbidity or mortality (excluding reexploration). RESULTS: 5016 patients were operated on between 2010 and 2014; of these, we included the records of 84 bleeding and 498 dry patients. Propensity matching resulted in 68 pairs of patients well-matched on baseline and operative variables. As compared to matched dry patients, bleeding patients were more likely to experience the primary outcome of any morbidity/mortality (36.8 vs. 13.2 %, p = 0.002), as well as ventilation >24 h (33.8 vs. 7.4 %, p < 0.001) and 30-day mortality (11.8 vs. 1.5 %, p = 0.02). Of the 84 bleeding patients, 46 underwent reexploration for bleeding within 24 h of surgery. A subgroup analysis propensity matching bleeding patients who were or were not reexplored <24 h demonstrated similarly poor outcomes in each group (primary outcome, 44.7 % reexplored vs. 50.0 % non-reexplored, p = 0.65), though reexplored patients were far less likely to require hematoma evacuation/washout >24 h after surgery (0 vs. 18.4 %, p = 0.005). CONCLUSIONS: Even among hemodynamically stable patients, severe bleeding is associated with markedly worse outcomes following cardiac surgery.

Early and late outcomes after surgical repair of congenital supravalvular aortic stenosis: a European Congenital Heart Surgeons Association multicentric study.

OBJECTIVES: Our goal was to evaluate the early and late results of the surgical management of congenital supravalvular aortic stenosis (SVAS). METHODS: We performed a retrospective, multicentre study using data from the European Congenital Heart Surgeons Association. Exclusion criteria were age >18 years, operation before 1990 and redo supravalvular aortic stenosis operations. Multivariate Cox regression analysis was performed to detect independent predictors of adverse events. RESULTS: Of a total of 301 patients (male/female = 194/107; median age 3.9 years, range 13 days-17.9 years), 17.6% had a prior surgical or interventional procedure. Pulmonary artery stenosis was present in 41.5% and coronary anomalies in 13.6%. The operation consisted of a single patch repair in 36.7%, a pantaloon-shaped patch in 36.7%, a 3-patch technique in 14.3% and other techniques in 11.7%. Postoperative complications occurred in 14.9%, and the early mortality rate was 5%. At a median follow-up of 13 years (interquartile range 3.5-7.8; follow-up completed 79.1%), there were 10 late deaths (4.2%). A surgical reoperation or an interventional cardiology procedure occurred in 12.6% and 7.2%, respectively. No significant differences in outcomes between the techniques were found. Age at repair <12 months and pulmonary artery stenosis were associated with an increased risk of early (P = 0.0001) and overall mortality (P = 0.025), respectively. Having an operation after 2005 and co-existing pulmonary artery stenosis were significant predictors of late reintervention (P = 0.0110 and P = 0.001, respectively). CONCLUSIONS: Surgical repair of congenital stenosis is an effective procedure with acceptable surgical risk and good late survival, but late morbidity is not negligible, especially in infants and when associated pulmonary artery stenosis is present.

Association of nadir oxygen delivery on cardiopulmonary bypass with serum glial fibrillary acid protein levels in paediatric heart surgery patients.

OBJECTIVES: Protecting the brain during cardiac surgery is a major challenge. We evaluated associations between nadir oxygen delivery (DO2) during paediatric cardiac surgery and a biomarker of brain injury, glial fibrillary acidic protein (GFAP). METHODS: Blood samples were obtained during a prospective, single-centre observational study of children undergoing congenital heart surgery with cardiopulmonary bypass (CPB) (2010-2011). Remnant blood samples, collected serially prior to cannulation for bypass and until incision closure, were analysed for GFAP levels. Perfusion records were reviewed to calculate nadir DO2. Linear regression analysis was used to assess the association between nadir DO2 and GFAP levels. RESULTS: A total of 116 consecutive children were included, with the median age of 0.75 years (interquartile range: 0.42-8.00) and the median weight of 8.3 kg (5.8-20.0). Single-ventricle anatomy was present in 19 patients (16.4%). Deep hypothermic circulatory arrest (DHCA) was used in 14 patients (12.1%). On univariable analysis, nadir DO2 was significantly associated with GFAP values measured during rewarming on CPB (P = 0.005) and after CPB decannulation (P = 0.02). On multivariable analysis controlling for CPB time, DHCA and procedure risk category, a significant negative relationship remained between nadir DO2 and post-CPB GFAP (P = 0.03). CONCLUSIONS: Lower nadir DO2 is associated with increased GFAP levels, suggesting that diminished DO2 during paediatric heart surgery may be contributing to neurological injury. The DO2-GFAP relationship may provide a useful measure for the implementation of neuroprotective strategies in paediatric heart surgery, including goal-directed perfusion.